Stroke is a major source of morbidity and mortality in the United States with 795,000 strokes per year. Sixty percent of strokes are ischemic in nature and 20% are cardioembolic in origin. Patients with heart failure (HF) and left ventricular (LV) systolic dysfunction have higher rates of thromboembolic events including embolic stroke and peripheral arterial thrombi compared with the general population. It is well known that a common cause of arterial emboli in heart failure patients is myocardial infarction (MI) and subsequent left ventricular (LV) mural thrombus formation. LV thrombus (LVT) formation is initiated by platelet deposition on the endocardial surface of akinetic or dyskinetic myocardium with endothelium that is dysfunctional secondary to an inflammatory response.
In the era prior to reperfusion therapy (thrombolytics and primary percutaneous coronary intervention), the risk of thrombus formation in the setting of an anterior MI was more than 50% according to autopsy and surgical findings. However, reperfusion therapy has demonstrated a reduction in the incidence of LV thrombus to approximately 10% in patients with anterior MI. Most of these thrombi develop within the first two weeks after an acute MI. However, the risk continues to be elevated thereafter. Those patients who develop an LVT are at high risk of an embolic event (odds ratio 5.5, 95% CI 3.0-9.8) compared to those without LVT. This risk is greatest in the first 3-4 months, but continues out to at least 96 months.
Global or regional stagnation of blood and endocardial injury is hypothesized to promote the development of LVT. In particular, studies have shown that the presence of LVT following acute infarction is related to the location and size of infarction and the presence of pump failure. Anterior wall infarctions typically result in a greater area of necrotic myocardium than do infarctions in other areas, and thus adversely affect global LV function to a larger extent. Furthermore, in contrast to inferior wall infarction, apical dyskinesia occurs frequently secondary to anterior wall infarction, and predisposes to regional stasis of blood.
The identification of high risk patients and the pharmacologic prevention of LVT formation is the key to preventing embolic events. Stratification of patients at risk for LVT formation is currently limited, and primarily based on global assessment of ventricular function and image based assessment of ventricular wall motion. Patients are considered high-risk for thromboembolism if they have (a) LVEF<30% and (b) an antero-apical wall motion abnormality or an LV aneurysm on imaging. However, even those patients with an LVEF of 30-40% are still at increased risk. Current guidelines recommend parental anticoagulation with heparin once an “at risk” patient is identified. Heparin has been shown to significantly lower the risk of LV thrombus formation from 32% to 11% in the pre-reperfusion era. Once the aPTT is 2-3 times the control value, oral anticoagulation with warfarin is instituted with a target INR of 2.5 (range: 2.0-3.0) [9]. Warfarin is continued for 3-6 months. The use of warfarin is associated with an 86% reduction in the rate of embolization.
The majority of patients presenting with an acute ST elevation myocardial infarction (STEMI) undergo invasive coronary angiography and implantation of a drug-eluting intracoronary stent. Medical therapy following implantation of a stent requires “dual anti-platelet therapy” using aspirin and clopidogrel or prasugrel for at least one year and often longer. In patients considered at high risk of LVT formation, current guidelines recommend adding heparin and then warfarin to dual-antiplatelet in post-MI patients who have undergone reperfusion therapy with intracoronary stenting. This so called “triple therapy” significantly increases the fatal and non-fatal bleeding risk to 22.6% in the first 30 days and remains above 20% out to 90 days, the window when patients are at highest risk of LV thrombus formation. Current risk stratification methods therefore result in the treatment of 10 patients to prevent LV thrombus in 1 patient while the risk of bleeding is 1 in 5. Clearly, more effective methods of risk stratification are needed.
It would therefore be advantageous to provide a diagnostic method to aid in selecting those patients most likely to benefit from triple therapy or similar therapies designed to reduce thromboembolic risk.